Tissue-Specific Dissociation of Diurnal Transcriptome Rhythms During Sleep Restriction in Mice

Abstract

Study objectives: Shortened or mistimed sleep affects metabolic homeostasis, which may in part be mediated by dysregulation of endogenous circadian clocks. In this study, we assessed the contribution of sleep disruption to metabolic dysregulation by analysing diurnal transcriptome regulation in metabolic tissues of mice subjected to a sleep restriction (SR) paradigm.

Methods: Male mice were subjected to 2 × 5 days of SR with enforced waking during the first 6 hours of the light phase. SR and control mice were sacrificed at different time points of the day and RNA preparations from the mediobasal hypothalamus (MBH), liver, and epididymal white adipose tissue (eWAT) were subjected to whole-genome microarray hybridization. Transcriptional rhythms were associated with changes in behavioral and physiological parameters such as sleep, body temperature, and food intake. Rhythm detection was performed with CircWave and transcription profiles were compared by 2-way analysis of variance and t-tests with Benjamini-Hochberg corrections.

Results: Clock gene rhythms were blunted in all tissues, while transcriptome regulation was associated with either clock gene expression, sleep patterns, or food intake in a tissue-specific manner. Clock gene expression was associated with apoptosis pathways in the MBH and with tumor necrosis factor alpha signalling in liver. Food intake-associated genes included cilium movement genes in the MBH and lipid metabolism-associated transcripts in liver.

Conclusions: In mice, repeated SR profoundly alters behavioral and molecular diurnal rhythms, disrupting essential signalling pathways in MBH, liver, and eWAT, which may underlie the metabolic and cognitive disturbances observed in sleep-restricted humans such as shift workers.

Keywords: Sleep restriction; circadian clock; liver; mediobasal hypothalamus; transcriptome; white adipose tissue..